The electrical activity of neurons is associated with rapid changes in the pH of brain extracellular fluid. Within milliseconds, a rise in extracellular H can be detected that is caused by activation of the plasma membrane calcium ATPase (PMCA), as it pumps calcium out of neurons in exchange for extracellular hydrogen ions. A significant increase in external pH can occur due to the inability of the fluid to buffer hydrogen ions in a fat time frame. This is because extracellular forms of the enzyme carbonic anhydrase, which catalyze the buffering reaction, are limited in activity. The significance of the rapid elevation o extracellular pH lies in the sensitivity of several membrane channels to hydrogen ions. In this application we propose that the activity of the PMCA in a single neuron results in a boost of the current through its own post-synaptic N-methyl-D-aspartate receptors (NMDARs). Pilot data suggest that both the amplitude and time course of current through NMDARs are modulated by the rise in surface pH generated by the same cell. Additional data suggest that hippocampal interneurons are subject to similar modulation, due to the pH sensitivity of their post-synaptic kainate receptors. Pyramidal neurons and interneurons will be studied these contexts, using ex vivo hippocampal slice preparations. The consequences of these pH shifts for network activity are addressed in the final aim of this application, which investigates a short-term enhancement of post-synaptic responses of CA1 pyramidal neurons in the slice model. This potentiation is especially pronounced in preparations with a knock out of the carbonic anhydrase 14 isoform, and is postulated to occur through a transient rise in extracellular pH, mediated via the PMCA. These concepts are extended to the pathological setting of seizure generation by use of brain slice preparations, as well as an in vivo mouse model. We hypothesize that the transition to seizure is fostered by an extracellular alkalosis, and mitigated by the expression of carbonic anhydrase 14. To accomplish these aims work will make use of animals with a deletion of specific carbonic anhydrases, and will employ transgenic mice with green fluorescence protein expressed in specific interneurons. The physiological significance of these studies lies in the increased understanding of short-term plasticity in the brain and local circuit function. Its translational impact is directly relevant to the epilepsies, as well as other disorders in which increased excitability and spreading depression have been implicated, such as migraine and the exacerbation of tissue damage after stroke and traumatic brain injury.